From the Center for Psychopharmacology, Diakonhjemmet Hospital.
J Clin Psychopharmacol. 2020 Mar/Apr;40(2):137-144. doi: 10.1097/JCP.0000000000001174.
The antidepressant venlafaxine is largely O-desmethylated by CYP2D6, whereas CYP2C19 mediates an alternative metabolic route of venlafaxine through N-desmethylation. The aim of this study was to investigate the combined effect of genotype-predicted CYP2D6 and CYP2C19 phenotypes on serum concentrations of venlafaxine and metabolites in a large patient population.
Patients were retrospectively included from a therapeutic drug monitoring service at Diakonhjemmet Hospital in Oslo (Norway) between January 01, 2007, and December 31, 2017. The study population was divided into different phenotype subgroups according to the combinations of CYP2D6/CYP2C19 phenotypes; intermediate metabolizers (IMs), poor metabolizers (PMs) and ultrarapid metabolizers, and compared using combined normal metabolizers (NMs) as reference.
The dose-adjusted serum concentration of venlafaxine was 4- and 13-fold increased in combined CYP2D6 IM/CYP2C19 PMs and combined PMs, respectively, compared with combined NMs (P < 0.001). The sum concentration of venlafaxine + ODV (pharmacological active moiety) was increased 1.9 and 3.6-fold, respectively, in the same phenotype groups. Furthermore, the dose-adjusted active moiety exposure was similar in combined IMs as combined CYP2D6 PM/CYP2C19 NMs. CYP2D6 and CYP2C19 phenotypes explained 46% of the interindividual variability in dose-adjusted venlafaxine serum concentrations, whereas CYP2D6 alone explained 24%.
The combined CYP2D6/CYP2C19 phenotype has a significant impact on serum concentrations of venlafaxine and also on the active moiety of venlafaxine + ODV, than CYP2D6 alone. In clinical practice, it is therefore important to take into account phenotype variabilities of both enzymes when assessing the risk of dose-dependent adverse effects during venlafaxine treatment.
抗抑郁药文拉法辛主要通过 CYP2D6 进行 O-去甲基化，而 CYP2C19 通过 N-去甲基化介导文拉法辛的另一种代谢途径。本研究旨在调查基因型预测的 CYP2D6 和 CYP2C19 表型对大量患者人群中文拉法辛血清浓度和代谢物的联合影响。
本研究回顾性纳入了 2007 年 1 月 1 日至 2017 年 12 月 31 日期间在挪威奥斯陆 Diakonhjemmet 医院治疗药物监测服务中接受治疗的患者。根据 CYP2D6/CYP2C19 表型的组合，将研究人群分为不同的表型亚组；中效代谢者（IMs）、弱代谢者（PMs）和超快代谢者，并以联合正常代谢者（NMs）作为参考进行比较。
与联合 NMs 相比，联合 CYP2D6 IM/CYP2C19 PMs 和联合 PMs 患者中文拉法辛的剂量调整血清浓度分别增加了 4 倍和 13 倍（P<0.001）。文拉法辛+ODV（活性药物成分）的总浓度在相同的表型组中分别增加了 1.9 倍和 3.6 倍。此外，联合 IMs 中的剂量调整活性药物成分暴露与联合 CYP2D6 PM/CYP2C19 NMs 相似。CYP2D6 和 CYP2C19 表型解释了文拉法辛剂量调整血清浓度个体间变异性的 46%，而 CYP2D6 单独解释了 24%。
与 CYP2D6 单独相比，联合 CYP2D6/CYP2C19 表型对文拉法辛的血清浓度以及文拉法辛+ODV 的活性药物成分有显著影响。因此，在临床实践中，评估文拉法辛治疗期间与剂量相关的不良反应风险时，考虑两种酶的表型变异性非常重要。
